Flunarizine, a Calcium Channel Blocker: a New Prophylactic Drug in Migraine

Amery, Willem K.

doi:10.1111/j.1526-4610.1983.hed2302070.x

Cited by 101 publications

(60 citation statements)

References 7 publications

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“…Ritanserin and SB 242084 are 5-HT2 receptor antagonists that are used for the treatment of neurological disorders (39)(40)(41). Flunarizine is a nonselective calcium entry blocker with histamine H1 receptor-blocking activity (42), and amperozide is an atypical antipsychotic with high affinity for 5-HT2 receptors (43). These compounds have not been shown to target any steps of the HCV replication cycle and therefore may be explored as new HCV therapeutic agents with potentially novel mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Novel Cell-Based Hepatitis C Virus Infection Assay for Quantitative High-Throughput Screening of Anti-Hepatitis C Virus Compounds

Lan

et al. 2014

Antimicrob Agents Chemother

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bTherapy for hepatitis C virus (HCV) infection has advanced with the recent approval of direct-acting antivirals in combination with peginterferon and ribavirin. New antivirals with novel targets are still needed to further improve the treatment of hepatitis C. Previously reported screening methods for HCV inhibitors either are limited to a virus-specific function or apply a screening method at a single dose, which usually leads to high false-positive or -negative rates. We developed a quantitative high-throughput screening (qHTS) assay platform with a cell-based HCV infection system. This highly sensitive assay can be miniaturized to a 1,536-well format for screening of large chemical libraries. All candidates are screened over a 7-concentration dose range to give EC 50 s (compound concentrations at 50% efficacy) and dose-response curves. Using this assay format, we screened a library of pharmacologically active compounds (LOPAC). Based on the profile of dose-dependent curves of HCV inhibition and cytotoxicity, 22 compounds with adequate curves and EC 50 s of <10 M were selected for validation. In two additional independent assays, 17 of them demonstrated specific inhibition of HCV infection. Ten potential candidates with efficacies of >70% and CC 50 s (compound concentrations at 50% cytotoxicity) of <30 M from these validated hits were characterized for their target stages in the HCV replication cycle. In this screen, we identified both known and novel hits with diverse structural and functional features targeting various stages of the HCV replication cycle. The pilot screen demonstrates that this assay system is highly robust and effective in identifying novel HCV inhibitors and that it can be readily applied to large-scale screening of small-molecule libraries.

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Section: Discussionmentioning

confidence: 99%

Novel Cell-Based Hepatitis C Virus Infection Assay for Quantitative High-Throughput Screening of Anti-Hepatitis C Virus Compounds

Lan

et al. 2014

Antimicrob Agents Chemother

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“…channel blocker that has been used to prevent migraine headaches [1], control intraocular pressure [2], and eliminate atrial flutter [3]. In addition, flunarizine possesses cytoprotective activity in some model systems.…”

Section: Introductionmentioning

confidence: 99%

The Ca2+ channel blocker flunarizine induces caspase-10-dependent apoptosis in Jurkat T-leukemia cells

Conrad¹,

Furlong²,

Doucette³

et al. 2010

Apoptosis

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Flunarizine is a Ca(2+) channel blocker that can be either cytoprotective or cytotoxic, depending on the cell type that is being examined. We show here that flunarizine was cytotoxic for Jurkat T-leukemia cells, as well as for other hematological maligancies, but not for breast or colon carcinoma cells. Treatment of Jurkat cells with flunarizine resulted in caspase-3 activation, poly (ADP-ribose) polymerase cleavage, and laddering of DNA fragments, all of which are hallmarks of apoptosis. Flunarizine-induced DNA fragmentation was inhibited by the caspase-3 inhibitor z-DEVD-fmk, the caspase-8/caspase-10 inhibitor z-IETD-fmk, and the caspase-10 inhibitor z-AEVD-fmk, but was not reduced in caspase-8-deficient Jurkat cells, indicating the involvement of caspase-10 upstream of caspase-3 activation. Interestingly, FADD recruitment to a death receptor was not involved since flunarizine caused DNA fragmentation in FADD-deficient Jurkat cells. Flunarizine treatment of Jurkat cells also resulted in reactive oxygen species production, dissipation of mitochondrial transmembrane potential, release of cytochrome c from mitochondria, and caspase-9 activation, although none of these events were necessary for apoptosis induction. Collectively, these findings indicate that flunarizine triggers apoptosis in Jurkat cells via FADD-independent activation of caspase-10. Flunarizine warrants further investigation as a potential anti-cancer agent for the treatment of hematological malignancies.

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“…The success of sumatriptan in migraine therapy stirred up the research interest in the field of migraine. Currently, prophylactic treatments for migraine include calcium channel blockers, 5-HT 2 receptor antagonists, beta adrenoceptor blockers and gamma-amino butyric acid (GABA) agonists (Amrey, 1983;Rogers et al, 2000). Unfortunately, many of these treatments are non-specific and not always effective (Goadsby et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

In vitro pharmacological investigations of Sapindus trifoliatus in various migraine targets

Arulmozhi

Sridhar

Bodhankar

et al. 2004

Journal of Ethnopharmacology

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Flunarizine, a Calcium Channel Blocker: a New Prophylactic Drug in Migraine

Cited by 101 publications

References 7 publications

Novel Cell-Based Hepatitis C Virus Infection Assay for Quantitative High-Throughput Screening of Anti-Hepatitis C Virus Compounds

Novel Cell-Based Hepatitis C Virus Infection Assay for Quantitative High-Throughput Screening of Anti-Hepatitis C Virus Compounds

The Ca2+ channel blocker flunarizine induces caspase-10-dependent apoptosis in Jurkat T-leukemia cells

In vitro pharmacological investigations of Sapindus trifoliatus in various migraine targets

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